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ISOTOPE EFFECTS

usually has no effect on the qualitative chemical reactivity of the substrate. replacement of an atom by one of its isotopes. often has an easily measured effect on the rate at which reaction occurs. ISOTOPE EFFECTS.

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ISOTOPE EFFECTS

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  1. usually has no effect on the qualitative chemical reactivity of the substrate replacement of an atom by one of its isotopes often has an easily measured effect on the rate at which reaction occurs ISOTOPE EFFECTS • A special type of substituent effect which has proved very valuable in the study of reaction mechanisms is the replacement of an atom by one of its isotopes. • Isotopic substitution most often involves replacing protium by deuterium (or tritium), but is applicable to nuclei other than hydrogen. • The quantitative differences are largest however for hydrogen, because its isotopes have the largest relative mass differences.

  2. those in which a bond to the isotopically substituted atom is broken in the rate determining step PRIMARY KINETIC ISOTOPE EFFECTS • Any C-H bond has characteristic vibrations which impart some energy to the molecule in its normal state. This energy is called the zero-point energy. • The energy associated with these vibrations is related to the mass of the vibrating atoms. Because of the greater mass of deuterium, the vibrations associated with a C-D bond contribute less to the zero point energy than those associated with the corresponding C-H bond. • For this reason substitution of protium by deuterium lowers the zero-point energy of a molecule.

  3. E R-H R-D • For reaction involving cleavage of a bond to hydrogen (or deuterium), a vibrational degree of freedom in the normal molecule is converted to a translational degree of freedom, and the bond is broken. • The energy difference due to this vibration disappears at the transition state. The transition state has the same energy for the protonated and deuterated species. TS DG‡D The deuterated molecule has the lower zero-point energy, so it has a higher activation energy to reach the transition state. DG‡H I

  4. MAXIMUM EFFECT SMALLER EFFECT CLOSE TO 1 HOW BIG IS ISOTOPIC EFFECT? IT DEPENDS ON THE NATURE OF THE TRANSITION STATE hydrogen being transferred is bond about equally to two other atoms at the transition state bond breaking more or less than half complete at the transition state the transition state is very reactant-like or product-like Calculated maximum for the isotope effect involving C-H bonds kH/kD = 7

  5. is a strong evidence that the bond to the substituted hydrogen atom is being broken in the rate determining step. kH/kD ≥ 2 the transition state must occur quite close to reactant or to product (early/late). the bond to hydrogen is either only slightly or completely broken at the transition state = good evidence that the transitions state involves strong bonding of the hydrogen to both its new and its old bonding partners WHAT INFORMATION GIVES US THE EXTENT OF PRIMARY ISOTOPE EFFECT? The magnitude of the isotope effect provides a qualitative indication of where the transitions state lies with regard to product and reactant Relatively low primary effect Isotope effect near the theoretical maximum

  6. kH/kD > 1 NORMAL kH/kD < 1 INVERSE those in which the substituted hydrogen atom is not directly involved in the reaction SECONDARY KINETIC ISOTOPE EFFECTS kH/kD = 0.7 - 0.15 • they are also classified a or b etc. depending on the location of the isotopic substitution wth respect to the reacting carbon. • secondary isotope effects result from a thightening or a loosening • of a C-H bond at the transition state. • The strenght of the bond may change because of a hybridization change.

  7. If sp3-hybridized carbon is converted to a sp2 as reaction occurs, a hydrogen bound to the carbon will experience decreased resistance to C-H bending. • The freeing of the vibration for a C-H bond is greater that for a C-D bond because the C-H bond is slightly longer and the vibration therefore has a larger amplitude. This will result in a normal isotope effect

  8. An inverse isotopic effect will occur if coordination at the reaction center increases in the transition state. The bending vibration will become more restricted. • Detailed analysis of isotope effects reveals that there are many other factors that can contribute to the overall effect in addition to the dominant change in bond vibrations. For that reason, it is not possible to quantitatively predict the magnitude of either primary or secondary isotope effects for a given reaction. Furthermore, there is not a sharp numerical division between primary and secondary effects, especially in the range between 1 and 2.

  9. ISOTOPES IN LABELING EXPERIMENTS • A quite different use of isotopes in mechanistic studies is their use as labels for ascertaining the location of a given atom involved in a reaction. • As in kinetic experiments the substitution of an isotope will not qualitatively affect the course of the reaction. • The nuclei most common used for isotopic tracer experiments in organic chemistry are deuterium, tritium, and the 13C and 15C isotopes of carbon.

  10. There are several means of locating isotopic labels. Deuterium can frequently be located by analysis of NMR spectra. In contrast to the normal 1H isotope, deuterium does not show any NMR signal under the usual operating circumstances. The absence of a specific signal can therefore be used to locate deuterium. • Tritium and 14C and other radioactive isotopes can be detected on the basis of the radioactivity. This is a very sensitive method. • 13C has become an important isotope for tracer experiments: unlike 12C, 13C has a nuclear magnetic moment and can be detected in NMR spectrometers. The appearance of a strongly enhanced 13C resonances permits assignments of the labeled positions. • This method avoids the necessity of developing a degradative scheme to separate specific carbon atoms, as for 14C.

  11. the breaking of the acyl bond or the breaking of the alkyl bond MECHANISM OF THE HYDROLYSIS OF ESTERS IN BASIC SOLUTION An example of the use of isotope labeling to understand the mechanism of a reaction is the study of the hydrolysis of esters in basic solution. Two mechanisms are possible for the hydrolysis:

  12. The rate low does not allows to choose one hypothesis or the other, because and it means that in the transition state both the ester and the OH- are present • a one-step direct attack of OH- to the ester Two different pathways are possible: • a two-step mechanism with a pre-equilibrium between OH- and the ester to give a complex, followed by a slow step in which the complex decomposes to give the products

  13. The breaking of the acyl bond can take place in both the pathways: while the breaking of the alkyl bond can take place only if the OH- attacks directly R’: Anyway both the pathways can be described by the experimental kinetic law, and this does not allows to understand which is the real mechanism.

  14. 18O is found in the final alcohol 18O is found in the final acid 18O labeling of the starting ester is useful in this case: 18O was found in the final alcohol, confirming that the real mechanism is the one in which the acyl bond is broken.

  15. REDUCTION OF THIAZOLIUM SALTS WITH NaBH4 Isotope labelling was used to stydy the mechanism of the reduction of N-alkyl thiazolium salts to N-alkylthiazolidines with NaBH4 in water. It was hypotized that the first attack of BH4- is in 2 position, giving the dihydroderivative, also on the basis of the observation that othe nucleoiphiles as OH- attack thiazolium salts at the same position. Furthermore in aprotic solvents only this tetrahydroderivative is obtained.

  16. The need for a protic solvent to complete the reaction leads to the hypothesis that the subsequent stage is a proton-transfer between the solvent and the dihydroderivative, on one of the two sp2 carbon atoms, with the positive charge supported by nitrogen or sulfur. The next stage would be again the attack of BH4- to give the tetrahydroderivative. The position in which the hydrogen atoms from the solvent or from the reducing agent are in the final product is different depending on the mechanism of the reaction and can be highlighted using deuterated reagents under appropriate conditions.

  17. a) By reducing 3-benzyl-4-methyl thiazole bromide with NaBH4 in D2O it was observed that the deuterium atom given by the solvent is in position 5. In theory it would be possible to clarify the structure of the product formed through mass spectrometry, but in protic solvents a faster H-D exchange at position 2 of the original product takes place.

  18. b) on the other hand reducing the same molecule with NaBD4 in H2O it was observed, on the basis of the NMR spectrum, that the final product actually contained 2 atoms of deuterium. In the product not deuterated the signal of the methyl is a doublet, due to the presence of the vicinal proton; In the deuterium containing product the same substituent gives a simple singlet and this indicates the presence of deuterium in vicinal position.

  19. c) The confirmation of the collected occurs with the reduction of the original product with NaBD4 in D2O: on the final product 3 deuterium atoms can be found, located by NMR and MS studies.

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